Central control analysis method of high performance liquid chromatography in preparation process of 1, 3-dimethyl propane diamidine dihydrochloride

Abstract

The invention discloses a central control analysis method of high performance liquid chromatography in the preparation process of 1, 3-dimethyl propanediamidine dihydrochloride, which comprises the following steps: in the preparation process of the 1, 3-dimethyl propanediamidine dihydrochloride, taking reaction liquid, adding a weakly alkaline buffer reagent, heating to 60-80 DEG C, fully deriving under an ultrasonic condition, filtering, washing and drying to obtain the 1, 3-dimethyl propanediamidine dihydrochloride. The method has the advantages that the residue of intermediate-state materials and the production amount of products in the reaction section process can be accurately analyzed through a high performance liquid chromatograph, so that the reaction endpoint is accurately judged, the reaction time is saved, the reaction yield is increased, the blank that no analysis method is used for monitoring the reaction process in the current preparation process of the 1, 3-dimethylpropanediamidine dihydrochloride is filled, and the method is suitable for industrial production. The method has important guiding significance on optimization of experimental conditions, and provides technical support for laboratory research and development and industrial production.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and in particular relates to a central control analysis method of high performance liquid chromatography in the preparation process of 1,3-dimethylmalonamidine dihydrochloride. Background Art

[0002] 2-Amino-4,6-dimethoxypyrimidine, commonly known as dimethoxypyrimidine or pyrimidineamine, is widely used in the synthesis of sulfonylurea herbicides, such as nicosulfuron, pyrazosulfuron, benzylsulfuron and pyrazosulfuron, among which nicosulfuron herbicide is used the most. Foreign pesticide manufacturers such as Bayer and DuPont purchase 2-amino-4,6-dimethoxypyrimidine, a key intermediate, from China for subsequent processing. In addition, considering the expansion of the production of nicosulfuron compound compound dicamba, the market demand for 2-amino-4,6-dimethoxypyrimidine may increase in the future.

[0003]

[0004] There are many synthetic routes for 2-amino-4,6-dimethoxypyrimidine, among which the malononitrile-cyanamide route is the mature industrial route at this stage. The malononitrile-cyanamide synthetic route is as follows:

[0005] The steps of the malononitrile-cyanamide process synthesis are as follows:

[0006] 1) Using malononitrile and methanol as raw materials and toluene as solvent, dry hydrogen chloride gas is introduced at a reaction temperature of 5 to 15°C for 22 to 30 hours, and the hydrogen chloride in the system is removed under reduced pressure;

[0007] 2) Slowly drop the 1,3-dimethylmalonamidine dihydrochloride reaction system into sodium bicarbonate or sodium carbonate solution for neutralization, strictly control the neutralization temperature at 5-15°C and the system pH at 5.5-6.8. After neutralization, phase separation is completed and the aqueous phase enters the next step of reaction;

[0008] 3) dropping cyanamide aqueous solution into the aqueous phase of step 2), strictly controlling the dropping temperature at 5-15° C., after the dropping is completed, heating to 20-30° C. to keep the temperature for reaction for 2-5 hours, and filtering to obtain a white cyanide solid;

[0009] 4) The cyanide solid in step 3) is dried at low temperature to remove water, added to toluene to reflux the reaction to complete, distilled to recover toluene, then cooled to 0-5° C. for crystallization, filtered and dried to obtain 2-amino-4,6-dimethoxypyrimidine.

[0010] 1,3-Dimethylmalonamidine dihydrochloride is an important intermediate for the synthesis of 2-amino-4,6-dimethoxypyrimidine. The reaction time for the synthesis of 1,3-dimethylmalonamidine dihydrochloride in this route is as long as 22 to 30 hours. In industrial production, a quantitative amount of hydrogen chloride is often introduced, and the reaction is judged to be completed at a certain time, and the next stage of reaction is entered.

[0011] Alternatively, the reaction supernatant is taken, an internal standard is added, and the remaining amount of the starting raw material malononitrile is quantitatively detected. When the content of malononitrile in the reaction supernatant is less than a certain value, it is determined that the reaction at this stage is completed.

[0012] However, there are intermediate states in the synthesis process of 1,3-dimethylmalonamide dihydrochloride, and the starting material malononitrile has reacted completely in the early stage of the reaction. Therefore, it is inaccurate to judge whether the reaction is completed at this stage by detecting the malononitrile content in the reaction clear liquid. The reaction process of 1,3-dimethylmalonamide dihydrochloride is as follows:

[0013]

[0014] Therefore, it is necessary to develop a new detection method to accurately monitor the progress of the reaction, which is very necessary to improve the yield of 1,3-dimethylmalonamide dihydrochloride. Summary of the invention

[0015] The purpose of the present invention is to provide a high performance liquid chromatography central control analysis method for the preparation process of 1,3-dimethylmalonamidine dihydrochloride, improve the accuracy of monitoring the reaction process, more accurately judge whether the reaction process of 1,3-dimethylmalonamidine dihydrochloride is completed, and improve the raw material conversion rate.

[0016] To achieve the above purpose, the technical solution of the present invention is as follows:

[0017] A high performance liquid chromatography in-process control analysis method for the preparation process of 1,3-dimethylmalonamidine dihydrochloride comprises the following steps:

[0018] 1) mixing the raw materials for preparing 1,3-dimethylmalonamidine dihydrochloride uniformly, introducing hydrogen chloride gas into the mixed raw materials for reaction, and taking the reaction liquid during the reaction;

[0019] 2) adding a weak alkaline buffer reagent to the reaction solution, heating to 60-80° C., ultrasonically treating for 5-10 minutes to obtain a hydrolyzate, and then adding methanol to the hydrolyzate and shaking to obtain a sample solution; the pH of the weak alkaline buffer reagent is 7-9;

[0020] 3) The sample solution was tested for the amount of hydrolysis product using high performance liquid chromatography

[0021] The following chromatographic separation conditions were used for separation;

[0022] Acetonitrile and 0.1wt% phosphoric acid aqueous solution were used as the mobile phase, and the elution conditions were:

[0023] Time Acetonitrile 0.1wt% phosphoric acid aqueous solution 0 3％ 97％ 5 3％ 97％ 15 60％ 40％ 22 60％ 40％ 22.01 3％ 97％ 30 stop

[0024] The chromatographic column is a SHIMADZU-GL WondaCract ODS-2 with a specification of 250mm*4.6mm*5um, or an Inertsil with a specification of 250mm*4.6mm*5um (UP). TM ODS-3;

[0025] The detection wavelength is 215nm to 240nm, preferably 215nm;

[0026] Column temperature is 35-45°C;

[0027] The injection volume is 5 to 10 uL;

[0028] The flow rate of the mobile phase is 0.8-1.5 mL / min;

[0029] Preferably, the reaction raw materials include malononitrile, anhydrous methanol and reaction solvent toluene; the molar ratio of malononitrile to anhydrous methanol is 1:2.4-3.0, and the amount of toluene used is 6-12 times the mass of malononitrile.

[0030] Preferably, the weakly alkaline buffer reagent is NH 3 ·H 2 O-NH 4 Cl solution, NaH 2 PO 4 -Na 2 HPO 4 Solution, KH 2 PO 4 -K 2 HPO 4 solution or boric acid-KCl-NaOH solution, preferably NaH 2 PO 4 -Na 2 HPO 4 Solution.

[0031] Preferably, NaH 2 PO 4 -Na 2 HPO 4 The total concentration of substances in the solution is 0.5-0.7 mol / L, of which NaH 2 PO 4 with Na 2 HPO 4 The molar ratio is 30-40:1.

[0032] The 1,3-dimethylmalonamidine dihydrochloride molecules, the intermediate material molecules and the HCl molecules contained in the reaction liquid are very acidic and will undergo hydrolysis reaction under the conditions of an overacidic (pH < 4) or overalkaline (pH > 10) aqueous system.

[0033] The main hydrolysis process of 1,3-dimethylmalonamidine dihydrochloride under peracid (pH < 4) aqueous system conditions:

[0034]

[0035] The main hydrolysis process of 1,3-dimethylmalonamidine dihydrochloride under the conditions of over-alkaline (pH>10) aqueous sodium hydroxide system:

[0036]

[0037] Under the conditions of peracid (pH < 4) and peralkali (sodium hydroxide system, pH > 10) aqueous systems, the final product of hydrolysis is malonic acid or disodium malonic acid. These two substances have basically no chromatographic absorption response under the conventional detection wavelength of 215-240nm, and the formation of hydrolysis products cannot be accurately detected, resulting in erroneous test results. At the same time, if the sample of the peracid system is directly injected, the HPLC chromatogram will have a bulging phenomenon.

[0038] Since the buffer contains a large amount of anti-alkali and anti-acid components, they consume a small amount of external strong acid and strong base through the movement of weak acid dissociation equilibrium, or resist the effect of slight dilution, so that the solution H + or OH - The concentration does not change significantly, so it has a buffering effect. Using a weakly alkaline buffer reagent to react with 1,3-dimethylmalonamide dihydrochloride molecules and HCl molecules contained in the reaction solution, and keeping the sample system in a stable pH range of 7 to 9, the hydrolysis reaction of dimethyl malonate in the aqueous system conditions of overacidity (pH <4) and overbase (pH >10) is effectively inhibited. The thermal hydrolysis process of 1,3-dimethylmalonamide dihydrochloride under such conditions:

[0039]

[0040] The main product of thermal hydrolysis of 1,3-dimethylmalonamidine dihydrochloride is dimethyl malonate (chromatographically normalized content 80-90%); by-product 1 is malonyl monomethyl ester monoamide (chromatographically normalized content 2-10%); by-product 2 is malonamide (chromatographically normalized content 2-10%). When monitoring the reaction endpoint, the above three products are combined and calculated as the generated amount of 1,3-dimethylmalonamidine dihydrochloride, and ammonia is released at the same time.

[0041] Thermal hydrolysis process of intermediate materials:

[0042]

[0043] The main product of thermal hydrolysis of the intermediate material is methyl cyanoacetate. When monitoring the end point of the reaction, methyl cyanoacetate is calculated as the remaining amount of the intermediate material, and ammonia is released at the same time. Studies have found that under the detection wavelength of 215-240nm, the four hydrolysis products of the intermediate material and 1,3-dimethylmalonamidine dihydrochloride have different degrees of absorption response, especially under the condition of 215nm, the four substances have good absorption response, good chromatographic peak shape, and stable baseline, which is the most suitable detection wavelength.

[0044] The present invention takes a reaction liquid of 1,3-dimethylmalonamidine dihydrochloride, adds a weakly alkaline buffer reagent, controls the system pH to 7-9, raises the temperature to 60-80°C, fully derivatizes under ultrasonic conditions, and drives out the generated ammonia. The remaining intermediate material and the generated amount of 1,3-dimethylmalonamidine dihydrochloride can be detected by high performance liquid chromatography separation.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] The invention adds a weak alkaline buffer reagent to a reaction liquid so that 1,3-dimethylmalonamidine dihydrochloride and an intermediate material are fully hydrolyzed into substances that are easy to detect, and uses a high performance liquid chromatograph to monitor the remaining amount of the intermediate material and the generated amount of the target product during the reaction process, so that the reaction endpoint can be judged more accurately, the reaction time is saved, the reaction yield is improved, and the blank that there is no accurate analysis method to monitor the reaction process during the synthesis process of 1,3-dimethylmalonamidine dihydrochloride is filled. The invention has important guiding significance for optimizing experimental conditions and provides technical support for laboratory research and development and industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the HPLC chromatogram of the test sample 1;

[0048] Figure 2 is the HPLC chromatogram of the test sample 2;

[0049] Figure 3 is the HPLC chromatogram of the test sample 3;

[0050] Figure 4 is the HPLC chromatogram of the test sample 4;

[0051] Figure 5 is the HPLC chromatogram of the test sample 5;

[0052] Figure 6 is the HPLC chromatogram of system adaptability solution sample 6 of Example 2;

[0053] Figure 7 is the HPLC chromatogram of system adaptability solution sample 7 of Example 2; DETAILED DESCRIPTION

[0054] The present invention will be further described below in conjunction with the embodiments and drawings.

[0055] The following examples and comparative examples all involve high performance liquid chromatography:

[0056] Chromatographic column: 250mm*4.6mm*5um(UP) Inertsil TM ODS-3.

[0057] HPLC: Agilent 1260

[0058] Acetonitrile and 0.1% phosphoric acid were used as the mobile phase, and the elution conditions were:

[0059] Time Acetonitrile Water (with 0.1% phosphoric acid) 0 3％ 97％ 5 3％ 97％ 15 60％ 40％ 22 60％ 40％ 22.01 3％ 97％ 30 stop

[0060] Detection wavelength: 215nm.

[0061] Column temperature: 40℃.

[0062] Injection volume: 5uL.

[0063] Mobile phase flow rate: 1.0 mL / min.

[0064] 1) Preparation of test sample solution, detection of raw materials and hydrolysis products:

[0065] Sample 1: Accurately weigh 50 mg of toluene (solvent), place in a 50 ml volumetric flask, dissolve in methanol, shake well, and set aside.

[0066] Sample 2: Accurately weigh 50 mg of malononitrile (starting material), place in a 50 ml volumetric flask, dissolve in methanol, and shake well for later use.

[0067] Sample 3: Accurately weigh 50 mg of methyl cyanoacetate (the thermal hydrolysis product of the intermediate material), place it in a 50 ml volumetric flask, dissolve it in methanol, shake well, and set aside.

[0068] Sample 4: Accurately weigh 50 mg of malonamide (1,3-dimethylmalonamide dihydrochloride byproduct 2), 50 mg of monomethyl malonamide (byproduct 1), and 50 mg of dimethyl malonate (main hydrolysis product), place them in a 50 ml volumetric flask, dissolve them in methanol, shake well, and set aside.

[0069] Sample 5: Accurately weigh 50 mg of toluene (solvent), 50 mg of intermediate material, 50 mg of 1,3-dimethylmalonamidine dihydrochloride, and 50 ml of weak alkaline buffer solution, heat to 60-80°C and ultrasonicate for 5-10 minutes, dissolve in methanol, shake well, and set aside.

[0070] Figure 1 to Figure 5 They are the HPLC chromatograms of samples 1 to 5 respectively.

[0071] Figure 1 The chromatographic peak at 24.948 min is toluene. Since toluene does not participate in the reaction, it is not considered for integration when monitoring the sample reaction endpoint.

[0072] Figure 2 The results show that no obvious chromatographic peaks are observed, indicating that malononitrile has no response in the liquid chromatography. In fact, in a normal reaction process, malononitrile has reacted completely in the early stage of the reaction without any residue.

[0073] Figure 3 The chromatographic peak at 8.385 min was methyl cyanoacetate.

[0074] Figure 4 It was shown that the chromatographic peak at 3.136 min was malonamide, the chromatographic peak at 5.147 min was malonyl monoamide, and the chromatographic peak at 15.227 min was dimethyl malonate.

[0075] Figure 5 It shows that the chromatographic peak at 3.132 min is malonamide, the chromatographic peak at 5.139 min is malonamide methyl ester, the chromatographic peak at 8.386 min is methyl cyanoacetate, the chromatographic peak at 15.203 min is dimethyl malonate, and the peak at 25 min is toluene (not integrated).

[0076] As can be seen from the figure, whether it is the detection of a single sample or the detection of a mixed sample of various standards (corresponding to the intermediate state and the hydrolysis product of 1,3-dimethylmalonamidine dihydrochloride), there is a good absorption response and a good baseline separation can be achieved. This shows that when the feed liquid is detected during the reaction process, there is no mutual influence between the substances on the test results, and each substance can be detected well.

[0077] Preparation of weak alkaline buffer solution: Accurately weigh NaH 2 PO 4 17.92g, placed in a 250ml volumetric flask, add water to dissolve and fix the solution to solution 1; accurately weigh Na 2 HPO 4 2.78g, placed in a 100ml volumetric flask, added water to dissolve and set to solution 2. Accurately pipette 230ml of solution 1 and 20ml of solution 2 and mix, pH = 8.02, concentration 0.565mol / L, for later use.

[0078] Example 1 Synthesis of 1,3-dimethylmalonamidine dihydrochloride

[0079] 1) Anhydrous methanol (74.82 g, 2.31 mol), malononitrile (60 g, 0.899 mol) and toluene (600 g, 10 w / w) were added to a 2 L dry four-necked flask, the temperature was lowered to 5-15°C, and dry hydrogen chloride (96.03 g, 2.61 mol) was introduced under temperature control. The entire ventilation time was 26 h, and the reaction liquid was sampled for in-process control analysis;

[0080] 2) Accurately weigh 0.250 g of the sample obtained at the end point of the small test reaction in Example 1, place it in a 250 ml volumetric flask, add 50 ml of a weak alkaline buffer solution, heat to 60-80° C., sonicate for 5-10 minutes, dissolve in methanol, shake well, and obtain a test solution for later use;

[0081] 3) The test liquid was tested according to the above HPLC conditions, and the results were as follows: Figure 6 As shown, the chromatographic peak at 3.160 min is malonamide, the chromatographic peak at 3.426 min is an unknown impurity, the chromatographic peak at 5.269 min is malonyl monomethyl ester monoamide, the chromatographic peak at 8.371 min is methyl cyanoacetate, and the chromatographic peak at 15.321 min is dimethyl malonate; each impurity, product, and intermediate can achieve good baseline separation; the remaining intermediate material and the generation of the product can be accurately seen, and the final calculation shows that the remaining intermediate material is 0.28%, the reaction is completed, and HCl is removed at -0.09 Mpa;

[0082] 4) Filter under nitrogen protection and dry in a reduced pressure oven to obtain 178.22 g of 1,3-dimethylmalonadiamine dihydrochloride dry product with a content of 99.12% and a yield of 96.79%.

[0083] Example 2 Synthesis of 1,3-dimethylmalonamidine dihydrochloride

[0084] 1) Anhydrous methanol (187.98 g, 5.833 mol), malononitrile (150 g, 2.26 mol) and toluene (1200 g, 8 w / w) were added to a 3 L reactor, the temperature was lowered to 5-15 ° C, and dry hydrogen chloride (240.07 g, 6.554 mol) was introduced under temperature control. The entire ventilation time was 22 h, and the reaction liquid was sampled for in-process control analysis;

[0085] 2) Accurately weigh 0.250 g of the sample obtained at the end point of the small test reaction in Example 1, place it in a 250 ml volumetric flask, add 50 ml of a weak alkaline buffer solution, heat to 60-80° C., sonicate for 5-10 minutes, dissolve in methanol, shake well, and obtain a test solution for later use;

[0086] 3) The test liquid was tested according to the above HPLC conditions, and the final calculation showed that the intermediate material remained 0.53%, the reaction was completed, and HCl was removed at -0.09Mpa;

[0087] 4) Filter under nitrogen protection and dry in a reduced pressure oven to obtain 446.38 g of 1,3-dimethylmalonadiamine dihydrochloride dry product with a content of 99.05% and a yield of 96.37%.

[0088] Comparative Example 1

[0089] 1) Anhydrous methanol (74.82 g, 2.31 mol), malononitrile (60 g, 0.899 mol) and toluene (600 g, 10 w / w) were added to a 2 L dry four-necked flask, the temperature was lowered to 5-15°C, and dry hydrogen chloride (96.03 g, 2.61 mol) was introduced under temperature control. The entire ventilation time was 26 h, and the reaction liquid was sampled for in-process control analysis;

[0090] 2) Accurately weigh 0.250 g of the sample obtained at the end point of the small test reaction in Example 1, place it in a 250 ml volumetric flask, add 50 ml of a weak alkaline buffer solution, heat to 60-80° C., sonicate for 5-10 minutes, dissolve in methanol, shake well, and obtain a test solution for later use;

[0091] 3) The reaction liquid was tested according to the above HPLC conditions, and the results were as follows: Figure 7 As shown, the chromatographic peak at 3.158min is malonamide, the chromatographic peak at 3.426min is an unknown impurity, the chromatographic peak at 5.25min is malonyl monomethyl ester monoamide, the chromatographic peak at 15.30min is dimethyl malonate, and no obvious chromatographic peak appears at 8.37min; but the peak height is relatively low.

[0092] The difference between Comparative Example 1 and Example 1 of the present invention is that the reaction liquid taken out is not treated with water, but with a buffer solution. From the test results, it can be seen that without adding a weakly alkaline buffer reagent for derivatization, a large amount of dimethyl malonate is hydrolyzed into malonic acid, and the intermediate state is also hydrolyzed into acid. Under this condition, the liquid chromatography has no response, resulting in inaccurate detection; and the baseline of the chromatogram appears.

[0093] Comparative Example 2 Synthesis of 1,3-dimethylmalonamidine dihydrochloride

[0094] Anhydrous methanol (75 g, 2.32 mol), malononitrile (60 g, 0.899 mol) and toluene (600 g, 10 w / w) were added into a 2L dry four-necked flask, and the temperature was lowered to 5-10°C. Dry hydrogen chloride (98.78 g, 2.68 mol) was introduced under temperature control. The entire ventilation time was 27 h. The reaction was completed and HCl was removed at -0.09 MPa. The mixture was filtered under a nitrogen protection device and dried in a reduced pressure oven to obtain 172.76 g of 1,3-dimethylmalonamide dihydrochloride dry product with a content of 98.82% and a yield of 93.54%.

[0095] In Comparative Example 2, the end of the reaction time was estimated only according to the reaction time, but there was actually some intermediate material remaining, and the yield of the finally obtained 1,3-dimethylmalonamidine dihydrochloride was low.

[0096] Furthermore, when the reaction time was 27h, the reaction liquid was taken and monitored and analyzed according to the detection method of the present invention. It was calculated that the intermediate material remained at 2.16% at this time, and the intermediate material had not reacted completely and should continue to react.

[0097] It is proved that the method of the present invention can accurately analyze the residual intermediate material and the product generation amount in the reaction section, so as to accurately judge the reaction endpoint, save reaction time and improve the reaction yield.

Claims

1. A high performance liquid chromatography in-process control analysis method for the preparation process of 1,3-dimethylmalonamidine dihydrochloride, characterized in that: The steps include: 1) mixing the raw materials for preparing 1,3-dimethylmalonamidine dihydrochloride uniformly, introducing hydrogen chloride gas into the mixed raw materials for reaction, and taking the reaction liquid during the reaction; 2) adding a weak alkaline buffer reagent to the reaction solution, heating to 60-80° C., ultrasonically treating for 5-10 minutes to obtain a hydrolyzate, and then adding methanol to the hydrolyzate and shaking to obtain a sample solution; the pH of the weak alkaline buffer reagent is 7-9; 3) The sample solution is tested for the amount of hydrolysis product using a high performance liquid chromatograph; The following chromatographic separation conditions were used for separation; Acetonitrile and 0.1wt% phosphoric acid aqueous solution were used as the mobile phase, and the elution conditions were: The chromatographic column is a SHIMADZU-GL WondaCract ODS-2 with a specification of 250mm*4.6mm*5um, or an Inertsil with a specification of 250mm*4.6mm*5um (UP). TM ODS-3; The detection wavelength is 215nm~240nm; Column temperature is 35-45°C; The injection volume is 5 to 10 uL; Mobile phase flow rate: 0.8~1.5mL / min.

2. The central control analysis method according to claim 1, characterized in that: The reaction raw materials include malononitrile, anhydrous methanol and reaction solvent toluene; the molar ratio of malononitrile to anhydrous methanol is 1:2.4-3.0, and the amount of toluene used is 6-12 times the mass of malononitrile.

3. The central control analysis method according to claim 1, characterized in that: The weak alkaline buffer reagent is NH3·H2O-NH4Cl solution, NaH2PO4-Na2HPO4 solution, KH2PO4-K2HPO4 solution or boric acid-KCl-NaOH solution, preferably NaH2PO4-Na2HPO4 solution.

4. The central control analysis method according to claim 2, characterized in that: The total concentration of substances in the NaH2PO4-Na2HPO4 solution is 0.5-0.7 mol / L, wherein the molar ratio of NaH2PO4 to Na2HPO4 is 30-40:1.

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